We have initiated a project to broaden the available fund of knowledge related to the effects of hydroxyurea (HU) on fetal hemoglobin synthesis in patients with sickle cell anemia by studying the acute and chronic responses associated with its administration to such individuals. These studies should provide insight into the pharmokinetics of HU, optimal dosage regimens, and predictive factors associated with the F-reticulocyte response. Preliminary results on 8 patients treated continuously for a period of 3 months disclosed several interesting points. First, despite close monitoring and the achievement of adequate serum drug levels, some patients (3 of 8, in our initial series) will not respond to hydroxyurea. Second, other patients, who cannot be distinguished by current biochemical or molecular analysis, will obtain significant elevations of HbF, especially after long periods of treatment. This lag in response suggests that mechanisms in addition to acute cytoreduction are involved in the effect of hydroxyurea on HbF production. Finally, the attainment of HbF levels in excess of 20-25%, in as pancellular a distribution as possible, may be necessary before objective indices of an improvement in microvascular pathophysiology are unambiguously stabilized or reversed. Should a significant sustained F-cell response be observed in select patients while on HU, it may be possible to increase further the magnitude of the response by simultaneously administering short courses of cloned human erythropoietin or cloned granulocyte-macrophage colony stimulating factor. In this fashion, one may approach fetal hemoglobin levels consonant with those observed in the benign HbS-HPFH phenotypes.